Preparation of ibuprofen-loaded chitosan films for oral mucosal drug delivery using supercritical solution impregnation
Graphical abstract
Introduction
Oral mucosal drug delivery nowadays has attracted great attentions, which could avoid hepatic first-pass metabolism and gastrointestinal drug degradation existed in oral administration (Bruschi and de Freitas, 2005). Moreover, oral mucosal drug delivery can achieve not only local drug delivery but also systemic drug delivery (Morales and McConville, 2011). The oral cavity has many advantages for oral mucosal drug delivery. For example, the oral mucosa is permeable with a rich blood supply, which can easily recover from stress of damage and has good patient compliance. The relatively low enzyme activity and the lack of Langerhans cells make the oral mucosa a suitable site for drug delivery (Shakya et al., 2011). For these reasons, various mucoadhesive formulations like disks (Jay et al., 2002), tablets (Llabot et al., 2002), gels (Ayensu et al., 2012, Şenel et al., 2000a), ointments (Petelin et al., 2004), patches (Nafee et al., 2003, Onishi et al., 2005), and films (Cui et al., 2007, Watanabe et al., 2009) have been developed. Among these formulations, films are especially flexible and elastic, making the patients more comfortable and compliable. Besides, films also ensure more accurate dosing of the drug compared to gels and ointments.
For successful oral mucosal drug delivery, the rapid elimination of the formulation due to the flushing action of saliva is a major difficulty, which limits its application in clinical therapy. This problem could be considered to be solved by using formulations based on mucoadhesive polymers. Mucoadhesive polymers are synthetic or natural macromolecules which could attach to mucosal surfaces to prolong residence time of the formulation (Grabovac et al., 2005), and it could also favor the drug absorption and localization to improve the bioavailability of drugs (Pedro et al., 2009). Chitosan is a typical mucoadhesive polymer due to the interaction between its positively charged amino groups and negatively charged sialic acid residues in mucus (Lee et al., 2000), and has been proposed as an ideal carrier in oral mucosal drug delivery (Abruzzo et al., 2012, Aksungur et al., 2004, Portero et al., 2007) due to its good biocompatibility, biodegradability and favorable toxicological properties (Bernkop-Schnürch and Dünnhaupt, 2012, Saranya et al., 2011). In addition, chitosan could enhance the absorption of drugs during trans-mucosa delivery by opening the tight junction (Şenel et al., 2000b), and demonstrate antimicrobial effect (Knapczyk and Macura, 1992).
In most cases, soaking the polymer matrices in a drug solution is a conventional method to make the drug-loaded formulation. However, this soaking method presents several drawbacks, such as possible use of toxic organic chemicals, undesired drug reactions, drug degradation, heterogeneous drug incorporation and low processing efficiency (Costa et al., 2010). In recent years, supercritical fluid has been proved to be an alternative green process for pharmacy and pharmaceutics (Pasquali and Bettini, 2008). Drugs could also be impregnated into polymer matrices by dissolving them in supercritical fluid (usually SCCO2), in which the binary mixture of drug and SCCO2 could facilitate the mass transfer in the drug loading process. After depressurization, the drug is entrapped in matrices, and finally homogeneous drug-loaded polymer matrices would be obtained. This process, known as supercritical solution impregnation (SSI), has been reported to be successfully implemented in fabricating several polymer based drug-loaded formulations. For example, flurbiprofen was impregnated in P(MMA-EHA-EGDMA) for ophthalmic drug delivery (Duarte et al., 2007); and PLLA film loaded with roxithromycin was used as an antibacterial implant (Yu et al., 2011). But the application of SSI in oral mucosal drug delivery was rarely reported. Compared with soaking method, SSI allows the drug impregnation of polymer matrices without altering or damaging their physical, chemical and mechanical properties and would not cause degradation of the impregnated drug (Costa et al., 2010). Moreover, drug loading can be controlled by the manipulation of several operational parameters. This method also permits SCCO2 to remove the residual of organic solvent used in the polymer matrices producing process (Reverchon et al., 2008). Therefore, more successful cases would be necessary to enrich this novel process in medical and pharmaceutical applications.
Ibuprofen is a non-steroidal drug used for anti-inflammatory and analgesic therapies, and it exhibits poor solubility in water and would stimulate the gastrointestinal tract in oral administration. In this study, ibuprofen is chosen as a model drug to prepare drug-loaded chitosan film formulations for oral mucosal drug delivery. The effect of SSI parameters on the morphology and drug loading capacity (DLC) of the chitosan film will be investigated. Finally, in vitro and ex vivo ibuprofen release profiles as well as bacterial inhibition of drug-loaded chitosan films are evaluated to indicate the potential application of the SSI process in the oral mucosal drug delivery.
Section snippets
Materials
Pseudomonas aeruginosa (ATCC 27853) and Staphylococcus aureus (ATCC 25923) were provided by Hangzhou Tianhe Microorganism Reagent Co., Ltd. (Zhejiang, China). Chitosan (deacetylation degree of 95%, viscosity of 186 mPa·s) was obtained from Golden-Shell Biochemical Co., Ltd. (Zhejiang, China), and ibuprofen (98% purity) was from Sangon Biotech Co., Ltd. (Shanghai, China). Carbon dioxide (99.99% purity) was supplied by Hangzhou Jingong Gas Co., Ltd. (Zhejiang, China). All other reagents were of
Chitosan film and its properties
Chitosan films were prepared by casting method, and Fig. 1 shows the properties of obtained chitosan films. From Fig. 1(a), the water-uptake of the films firstly increased dramatically, and the chitosan film seemed to be fully swollen and hydrated within 15 min. This was due to the porous structure and the hydrophilicity of the chitosan film, indicating a strong hydration of chitosan which would facilitate its rapid mucoadhesion in drug delivery. After 15 min, the water-uptake decreased slowly
Conclusions
Mucoadhesive ibuprofen-loaded chitosan films were successfully prepared using SSI process, which had high water-uptake and antibacterial effects and were suitable for oral mucosal drug delivery. The DLC and morphologies mainly depended on the SSI processing conditions, and could be tailored by SSI process. The ex vivo release study showed that the formulations could deliver ibuprofen across the rabbit buccal mucosa in a sustained- and controlled- manner. SSI could be amenable for processing
Acknowledgement
The authors would thank gratefully for financial support provided by the National Natural Science Foundation of China.
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